Project Summary/Abstract Animal viruses share two important features; a) an efficient system for delivering their genome to the target cell usually involving an activation process in the virion and b) a means of interacting with the adaptive immune system of the host. The structural and biophysical studies detailed here will show how the noroviruses have evolved capsids that perform both functions. Human noroviruses are responsible for almost a fifth of all cases of gastroenteritis worldwide. Noroviruses generate new strains every 2-4 years that cause worldwide epidemics. In the US alone, annually there are ~20 million cases and more than 70,000 hospitalizations of children. Efforts for a vaccine have been hindered by a lack of detailed structural information about antibody binding and the mechanisms of antibody escape. In addition, containment of the disease is also problematic since as few as ten virions are sufficient to infect a normal adult. Understanding all of these processes has been difficult with human noroviruses because of the lack of a tissue culture system and small animal model. To this end, we will be using the highly tractable mouse norovirus system where we have a cell culture system and an infectious clone. With regard to the first function of a viral capsid, we present evidence that noroviruses appear to undergo an apparent activation process where the addition of bile salts causes the protruding domain (P domain) to rotated and move ~16 onto the surface of the shell. This movement is correlated with greatly enhanced binding of the virus to the cell. In terms of the second function of a viral capsid, we also present evidence that the P domain itself is highly plastic and that this motility plays an integral role in receptor binding and antibody escape. Therefore, the studies presented here will not only elucidate a very unique norovirus activation process, but also how the virus evades the immune system. Together, this information could be leveraged in the future to develop vaccines and therapeutics for this serious disease.